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| Metastatic melanoma cells |
It's a safe prediction that immuno-oncology (IO) drug development activity
is unlikely to diminish in 2018, with a major objective being the validation
and approval of agents that synergise with the established
anti-CTLA-4 and anti-PD-1/PD-L1 immune checkpoint inhibitors.
Much has been written on the broad utility of inhibitors of indoleamine-2,3-dioxygenase-1
(IDO), an intracellular enzyme present in both immune cells and cancer cells
and which regulates tryptophan levels in
the tumour microenvironment (TME).
Depletion of tryptophan by upregulated IDO
expression starves cancer-antigen specific T cells, while a rise in the
concentration of tryptophan metabolites triggers the development of immunosuppressive
Treg cells.
This central role in local immunosuppresion and the prospect of synergy
with immune checkpoint inhibitor treatment and other immunotherapies has made
IDO (along with a similar enzyme, tryptophan-2,3-dioxygenase
2- TDO) an attractive target for IO drug development,
and a variety of orally available small
molecule inhibitors have entered clinical evaluation as both monotherapy and in
combination with immunotherapies or cytotoxic cancer drugs.
Big pharma interest in IDO and TDO
inhibitors has fuelled several “big headline” partnering deals, including BMS and Flexus Biosciences ($1.25 billon);
Roche and CuraDev Pharma ($555m); Roche and NewLink Genetics ($1 billion), and
Incyte Pharma and Roche, AstraZeneca, Merck and BMS (undisclosed terms).
IDO inhibitor progress has been mixed. In June last year, Roche returned
the rights to NewLink's navoximod (GDC-0919), the latter failing to meet any of
the primary study objectives (overall survival, progression-free survival or
objective response rate) when combined with taxane chemotherapy in breast
cancer patients. Combination with
Roche's ant-PD-L1 immune checkpoint inhibitor, Tecentriq® did not achieve an
overall response rate better than Tecentriq® alone in patients with advanced
solid tumours. Absence of efficacy was cited by iTeos Therapeutics today as the
reason for termination of an IDO development partnership with Pfizer following
analysis of interim trial data from a Phase I monotherapy study in patients with
malignant glioma.
Failure in cancer drug development is, unfortunately, the norm rather than
the exception, and it's possible that other IDO inhibitors with different
chemistries and better bioavailability may prove capable of either upping the
response to immune checkpoint inhibitors or being valuable treatments in their
own right. Phase II data from a study of Incyte's epacadostat in combination
with anti-PD-1 (Keytruda®) hinted that the combination might prove superior to,
and safer than, combined anti-CTLA-4 (Yervoy®) and anti-PD-1 therapy in
patients with advanced melanoma. A Phase III study (NCT02752074) is underway in
collaboration with Merck, with primary data anticipated around the middle of
2018.
AstraZeneca, a company which could stand some good IO related news,
recently expanded its collaboration with
Incyte to include lung cancer studies in combination with the anti-PD-L1
checkpoint inhibitor, Imfinzi®; other companies, including Kyowa Kirin,
Jubilant Biosys, Kyn Therapeutics and e-Therapeutics have recently entered the IDO/TDO
inhibitor game.
The apparent failure of
ITeos's candidate might not give immediate
cause for concern (glioma is a very hard target), but it's reasonable to
suppose that there are many fingers crossed in pharma management meetings in
the hope that Incyte's Phase III study leads to registration and paves the way
for the first small molecule IO treatments.
Photo credit: National Cancer Institute
